Substituted phenylpropylamines



Patented Dec. 15, 1953 Arlo Wayne Ruddy, Morristown; N. J'., Theodore J Becker, dece as ed', late of Delmar,,N Y., by

Maurice L.- Tainter, administrator, Albany, I.-Y., assignors to Winthrop-Spams rm, New

York, N. Y., a corporation of Delaware No "Drawing; Application J axillary? 28, 1949; SerialNo. 73,443

20 01 (CL 2 L296) This invention relates to basic compounds and their salts which are useful as antispasmodic agents, and to intermediates used in preparing the same. More particularly it re1ates.to-compounds having the general structure.

wherein R; is an all-:=yl',\a-1kenyl= or cycloalkyl radical, Y is an ethylene group which may besubstituted with alkyl groups, and -N=B represents. a tertiary amino group; and to non-toxis salts thereof. This'inventioniisa continuation-impart of the copendin'gapplication of A. WtRudd 'and T. J Becker, Serial Number651-,:6l6; now abandoned.

The purpose of antispasmodic" agents is tore-'- lieve spasms of the smooth muscles. These" spasms may be caused ('1 by exaggerated im-' pulses from the autonomic. nervous system which create violet contractions in the muscle or (2) stimulation of themuscle by chemical changes in the surrounding tissues. Atropine has the'ability of relieving thefirst type of spasms,v and its ac tion is thereforekn'own as neurotropic. Papav-' erine counteracts spasms of the second typeand hence its action is musculotropi'c.

The compounds have been studied for their" ability to redu'cespasms eliotedin'smooth muscle by barium chloride and acetylcholine in strips of rabbit ileum and by histamine in guinea pig.

ileum, and compared to atropineandupapeverine for their neurotropic and musculotropic: effects;v

respectively. These compounds have in general several times the musculotropic antispasmo'dic activity of papeverine without having increasedv toxicity over the latter. Furthermore, the compounds of this invention are characterized in general by moderate atropine-like action; However, they do not exhibit except to a very slight degree the often undesirable parasympathetic actions of atropine, such as mydriasis andcentral nervous system effects.

Compounds of the hereinabove disclosed formula, (C6H5)RCII--YN=B, may b conveniently synthesized through the intermediate carbinol (CsI-I)'RC'(OII) -Y-N=B which is prepared by treating a ketone of the general structure CsH5CO'-YN B, wherein the substituents have the meanings disclosed hereinabove, with an organometallic complex such as a Grignard reagents or an aryl'sodium compoundhaving the formula RM, where R has themeaning given above and M represents a metal such as sodium or lithium or a halogen-metal group such as bor'momagnesium; Alternatively, theketone may havefthe: structure R-COY-N=B' and the organometallic compound the formula CsHsMa Such reactions result in the fomnation of amino alcohols having: the structure- (Cami RIC(0H-) Y*-N=B The intermediate carbinols are disclosed and claimed inthe copending appiication of: A-.- W.

Buddy: and T. J-;. Becker, Serial-No; 735142, filed January 28,1949,

The'following equation i-llustratesa representative' overall reaction; that betweencyolohexyl magnesium bromide and beta-dimethylaminwbutyrophenone; and subsequent hydrolysis of the intermediate complex which is formed-:

zoon'ntr er-p 206E5COCH1OE-OH3 The aminoalcoh'ols may be reduced by avarie'ty' of methods, such as treatment withhydri'o'di'c acid and phosphorus; to amine of the formula GQI-I5) RCH'-Y --I I='B', the groups having the samesi'gnificance as-above;

In the formulas above disclosed, R- may repre-- sent cycloalk -yl groups; such as cyclohexyl and cycl'o'p'enty-l' and simplehydrocarbon substituted product'sthereof;- and alk-yl and alkenyl groups of at least four and preferably between four and may be termed alplialbeta-alkylene radicals; alpha; indicating one of the carbon atoms inthe aboveformula andbe'ta indicating the adjacent" carbon atom; The term alpha,beta-' distin== alkykneradicals having the free valence bonds onlyon adjacent carbon atoms guishes alkylene radicals of the above type from those in which the free valence bonds are not on adjacent carbon atoms of the radicals. The grouping --N:B represents an aliphatic amino group, -NB'R, including dialkylamino groups, the component organic groups R. and B being if desired of diirerent structure. The radicals R and R" together with the nitrogen atom may form a cyclic amino grouping such as piperidyl, morpholinyl, pyrrolidyl, piperazyl, thiamorpholinyl, and the like. Such cyclic amino groups may be considered aliphatic heterocyclic amino radicals, since they do not have complete, conjugate unsaturation, and do not exhibit aromatic properties (cf., Gilman, Organic Chemistry, 2d edition, vol. I, pp. 126-127, 1943), and behave like simple aliphatic amines.

In the synthesis of amino alcohols of the type hereinabove shown from ketones having the general structure by reaction with an organometallic compound of the type RM or CsHsM respectively (the substituents having the meanings already given), the

organometallic compound may be any of the usual forms which react with ketones to form tertiary alcohols. These types include the Grignard reagent, in which M stands for the group Mg-halogen; the alkyland aryl-sodium, -potassium or -lithium compounds, wherein M stands for Na, K, Li respectively; and related compounds. The amino ketones may be used as the free bases or as their salts, e. g., their hydrochlorides. When salts of the amino ketones are used, part or the organometallic compound is consumed by the acid, but this is not a serious disadvantage since an excess of the organometallic reagent is generally employed.

The amino ketones, which are the starting materials for the preparation of the amino alcohols and the amines which constitute our invention, may be synthesized by a variety of methods well understood by those skilled in the art. A simple method is based on the Mannich reaction and is illustrated by the preparation of beta-(diethylamino)-isopropyl cyclohexyl ketone from ethyl cyclohexyl ketone, formaldehyde and diethylamine hydrochloride.

A second method involves use of the Friedel- Crafts reaction of beta-(tertiary-amino) -acyl' halides with aromatic compounds by the method of Dalmer et al. (German Patent 629,054). For example, beta-dimethylaminobutyric acid [Decombe, Ann. chim. (10), 18, 145 (1932)] is converted by treatment with thionyl chloride to its acid chloride hydrochloride and the latter condensed with benzene in the presence of aluminum chloride to form beta-dimethylaminobutyrophenone.

A third synthetic approach utilizes the addition of amines to alpha,beta-unsaturated ketones, forming beta-amino ketones. An example of this process is the addition of piperidine to crotonophenone to form beta-piperidylbutyrophenone.

The conversion of the tertiary amino alcohols of the type (CsH5)RCOH-YN=B into amines having the structure (CcHs) RCHYN:B may be accomplished by several simple and generally applicable methods. The most direct is reduction with phosphorus and hydriodic acid. By this method the hydroxyl group is replaced by hydrogen in one operation. Another process is the dehydration of the tertiary amino alcoholto an 1 phenylacetonitrile (benzylcyanide) unsaturated amine and the reduction of the latter to the desired amine. Suitable agents for the dehydration are acetic anhydride, benzoyl chloride, concentrated hydrochloric acid in glacial acetic acid, and concentrated sulfuric acid. The reduction is conveniently achieved by catalytic hydrogenation or" either the amine or one of its salts. A third process of preparing the amine from the amino alcohol is by replacing the hydroX'yl group by a halogen and reductivcly cleaving the latter. The halogenation is effected by such agents as acetyl chloride, thionyl chloride, phosphorus tribromide and the like. The reductive cleavage can be effected either by catalytic hydrogenolysis, preferably using a palladium catalyst or by chemical methods, such as by sodium in alcohol reduction.

The conversion of the amino alcohols to amines is illustrated by the following reactions which can be applied to any of the amino alcohols disclosed herein:

By treatment with phosphorus and hydriodic acid in glacial acetic acid l-cyclohexyl-Lphenyl- 2-methyl-3-dibutylaminc-l-propanol is converted to 1-cyclohexyl-1-phenyl-2-methyl 3 dibutylaminopropane; and 1-phenyl-1-cyclohexyl-2,2- dimethyl-B-(N piperidyl) -l-propanol is converted to 1-phenyl-1-cyclohexyl-2,2-dirnethyl-3- (N-piperidyl) -propane.

It is not necessary to proceed through the carbinol intermediate to prepare the compounds of this inventtion. An often more convenient process, having the further advantage of often giving better yields, comprises successively alkylating and finally cleaving off the cyano group, thereby replacing it by hydrogen. Thus, alkylation of phenylacetonitrile with a cycloalkyl, alkyl or allrenyl halide gives a compound of the formula (C6H5)RCHCN. This is further alkylated with a tertiary-aminoalkyl halide to give (CsH5)RC(CN)-YN==B. Treatment of this nitrile with sodium amide gives the desired product (C6H5)RCHY-N:B. There is no need for the alkylations to take place in the order given, although it is preferred to introduce the aminoalkyl group last, since possible side reactions are thereby minimized. For example, phenylacetonitrile is condensed with isobutyl bromide in the presence of sodium amide to give phenylisobutylacetonitrile. The latter when condensed with N-piperidylethyl chloride under similar conditions gives phenylisobutyl-(N-piperidylethyl) acetonitrile. Cleavage of the cyano group, thereby replacing it by hydrogen, is effected by heating the trisubstituted nitrile with sodium amide, thus producing N-(5-methyl-3- phenylhexyl) -piperidine.

NaNHz NaNHa Examples of'crganic' halides'which may :beused to 'introducethe group R into the alph'a-position" be employed because of the unreactivity of vinyl and substituted vinyl halides This can be accomplished, however; by condensation of pheny1- acetonitrile with an aldehyde'or ketcne by-th'egeneral method of Murray and Cloke; J-I Am.

Chem. Soc. 58, 2016(1936) to give an alk'ylidene-- phenylacetonitrile. This may be alkylated with a tertiary-aminoalkyl halide, the double bond 1 then shifting into the vinyl position; For exampie, condensation of isobutyraldehyde with phenylacetonitrile gives isobutylidenephenylacetoni trile, which in turn can be alkylated with beta- (N-piperidylethyl) -chloride.

CHQCHCHI/ CtHsQHaON o=onorr orm H,

CtHs-CN GHQ-010E; CHzgCHCHa NaNHe H CH +CSHIDNCHBOHBCI 1 I CaHaC-CHfiBENCaI-Iw CaHs-U-CN' beta dimethylaminoethyl phenylacetonitrile, isobutyl betaethylmethylaminoethyl phenyle acetonitrile, isobutyl betadiethylaminoetliyl-'. phenylacetonitrile, isobutyl- (alpha-methyl betadiethylamino) ethyl phenylacetonitrile, isobutyl beta dipropylamino ethylphenylacetonitrile, isobutyl beta dibutylaminoethylphenylacetonitrile, isobutyl-beta-(Nepiperidyllethyl-phenylacetonitrile, isobutyl-beta- (N -pyrrolidyl) -ethyl-pheny1acetonitrile, and .isobutyl- (N-morpholinyl) -ethyl-phenylacetonitrile..

When the above named. nitriles are treated with sodium amide to replace the cyano group; by hydrogen, the following amines are produced.

respectively: N,N-dimethyl-3-phenyl-.5-methylhexylamine; N ethyl N, methyl 3 phenyl-,-

5 methylhexylamine; N, N diethyl 3 phenyle 5 methylhexylamine; N ,N diethyl 3-: phenyI-J 2,5 dimethylhexylamine; N,N dipropyli- 3' phenyl 5 methylhexylamine; N;N:"- dibutyl 1 3 phenyl 5 methylhexylamine; N 5-- (3v phenyl -5 methylhexyl) piperidi'ne N (3 phenyl 5 methylhexyl) pyrrolidine; and; N- --(3 phenyl 5 methylhexyl) morpholinap.

In the case of. compounds whereinR. is. 'axcy-r clohexyl radical, a variation of the nitrile*syn thesis may be used; Alkylationiof diphenyl-lacetonitrile with a tertiary-an'1inoall:yl'J'halidev produces a nitrile of the formula After replacement of the cyano group; with hy drogen byuse of sodium amide; one of thephenyl. groupsis selectively hydrogenated catalyticallyi; to a-cyclohexyl radical, giving Alternatively, diphenylmethane is alkylated withan aminoalkyl halide in the presence of a strong; base, such as sodium phenyl, as a condensing agent. This gives the"diphenylpropylamine directly which is then selectivelyhydrogenatedzto the phenylcyclohexyl derivative.

When used as pharmacological agents, these compounds are-ordinarily used in the form of Water-soluble salts, acid-addition salts derived from inorganic or organic acids, or quaternary saltsobtained by additionof alkyl or aralkyl esters .of inorganic acids, the anions of which are" non-toxic and otherwise innocuous to the ,ani-, mal organism at the dosage levels required for therapeutic results. Examples of such salt form-. ing substances include hydrochloric acid, hydro. bromic acid, hydriodic acid, sulfuric acid, citric acid, tartaric acid, lactic acid,,sulfamic acid, ethanesulfonic acid, etc.

The quaternary ammonium salts of the-basic nitriles, (CsH5)RC(CN)-Y-N=B, and the-ter tiary-amines, (CeH5-)RCH-YN=B, are derived from addition of alkyl or aralkyl esters of 'inor--- garlic acids or certain strong organic acids such 1 as sulfonic acids; Such salt-formingsubstances include methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide; propyl chloride, propyl bromide, propyl iodide, isopropyl bromide, butyl chloride, butyl bromide;

isobutyl bromide, sec.-butyl bromide, n-amyl bromide, n-hexyl chloride, benzyl chloride, hen-- zyl bromide, methyl sulfate, ethyl sulfate, methyl benzenesulfonate, methyl p toluenesulfonate, etc., which Will react directly with any of the above named basic nitriles or tertiary aminesto give respectively the methochlori e, methobromide, methiodide, ethochloride, ethobromide, ethiodide, propoohloride, propobromide, propiodide, isopropobromide, butochloride, butobro mide, isobutobromide, sec-butobroznide, n-amobromide, n-hexochloride, benzochloride, benzebromide, methosulfate, ethosulfate, methobenzenesulfonate, metho-p-toluenesulfonate, etc.

The quaternaries are generally prepared by Warming the free base with an excess of the saltforming ester in an inert organic medium such. as benzene or ether. The quaternary ammonium salt will separate, usually as a crystalline product, or canbe made to precipitate by the addition of other solvents or by concentration of the solu-. tion.

Alternatively, it is possible by use of metathetical reactions to replace the anion of a quaternary. by a different anion withoutreconversicn to the free base. This is usually effected by'treatment of a'solution of the quaternary, QX, with silver' oxide (hydroxide). The silversalt, AgX, isprecipitated leasing in solution; the :quaternary 1 hy- 1 droxide;:QOH:- .It is.- prerequisite,:ofizourse,ethat the salt AgX be insoluble in water. The quaternary hydroxide may then be neutralized with the appropriate acid to give any desired salt. For example, methiodides are generally easier to prepare by direct addition than methochlorides. Methyl iodide reacts more readily and is more convenient to use than methyl chloride. However, the methochloride may be readily prepared from the methiodide by the method just described. Treatment of a solution of the methiodide with silver oxide precipitates silver iodide leaving a solution of the quaternary hydroxide. Neutralization of this solution with hydrochloric acid gives the methochloride which can be obtained by concentration of the solution.

The following examples will illustrate my invention more completely but should not be construed as a limitation thereto.

Example 1 (a) 1 phenyl 1 cyclohexyl 2 methyl 3- (N-piperidyl) -l-propanol:

CoHn

CaH5-CCiICHzNC5I-Im on CH3 To a cold solution of cyclohexylmagnesium bromide, prepared from 193 g. (1.186 moles) of cyclohexyl bromide, 32.2 g. (1.326 moles) of magnesium and 600 cc. of anhydrous ether, was added in one and one-half hours at 0 C. 111 g. (0.479 mole) of alpha-(piperidyhnethyl)-propiophenone in 380 c. of dry benzene. After the addition, the reaction mixture was warmed to 73 C. while the ether was removed by distillation over a period of two and one-half hours and then added to ice containing 170 cc. of concentrated hydrochloric acid. Ammonium chloride (100 g.) and 350 cc. of 28% ammonium hydroxide were added and the organic layer was separated. The 1 aqueous layer was extracted with ether and the combined extracts were dried with anhydrous sodium sulfate. The solvent was removed and the residue distilled in vacuo. The base distilled at 180-195 C. (1 mm.) and solidified in the receiver. Recrystallization from methanol yielded 133 g. of base having M. P. l16-1l7 C. The hydrochloride was formed by adding dry ether to an absolute alcoholic solution of the base containing excess hydrogen chloride and melted at 259 C. with decomposition.

Anal. Calcd. for C21H34ONC1: Cl, 10.07; N, 3.90. Found: Cl, 10.12; N, 4.08.

(b) N (3 phenyl 3 cyclohexyl 2 methylpropyl) piperidine:

A mixture of 221 g. of l-phenyl-l-cyclohexyl- 2 methyl 3 (N piperidyl) 1 propanol, 27.9 g. of red phosphorus, 210 cc. of 47% hydriodic acid and 550 cc. of glacial acetic acid was refluxed for three hours. The reaction mixture was filtered through a sintered glass funnel, the funnel was washed with hot glacial acetic acid and the combined filtrates were treated with a small amount of sodium bisulfite and slowly diluted with 1400 cc. of warm water and chilled. The hydroiodide of the product crystallized out and was removed by filtration and washed with water. It was suspended in water, made alkaline with a solution of 60 g. of sodium hydroxide and stirred with ether for several hours. The ether aqueous layer was extracted with more ether and the combined extracts dried over anhydrous sodium sulfate. The ether was then evaporated and the residue distilled giving 178 g. of N (3 phenyl 3 cyclohexyl 2 methylpropyD-piperidine, B. P. 158-164" C. (1 mm); n =1.5364.

The free base was converted to its hydrochloride by dissolving in cc. of anhydrous alcohol and neutralizing to Congo red with cc. of 20% alcoholic hydrogen chloride. Upon addition of 700 cc. of anhydrous ether, one racemate of the hydrochloride precipitated, giving 52.4 g., M. P. 223-225 C. (dec.

Anal. Calcd. for C21H34NC1: Cl, 10.55; N, 4.17. Found: Cl, 10.60; N, 4.02.

After concentration of the filtrate a second crop of crystals was obtained, 17.3 g., M. P. 216 (doc). The remaining mother liquors were evaporated and the crystalline residue, 30.6 g., M. P. 170-176 C. was recrystallized from ethyl acetate, giving a sample of the other racemate of the hydrochloride of N-(B-phenyl-B-cyclohexyl- 2-methylpropyl)-piperidine, M. P. 178-180 C.

Anal. Calcd. for C21H34NC1I Cl, 10.55; N, 4.17. Found: Cl, 10.68; N, 4.07.

Example 2 (a) l-phenyl 1 cyclohexyl-Z-(N-piperidylmethyl)-l-butancl was prepared according to the method of Example 1, part (a) starting with 15.2 g. of alpha-(N-piperidylmethyl)-butyrophenone, P. l24-l26 C. (1 mm.), and 189 g. of cyclohexyl bromide. The free base had the P. P. Pit-185 C. (1 mm.) and the M. P. 86-87 C. Its hydrochloride had the M. P. 237-238.5 C.

Anal. Calcd. for C22H3GONC1I C, 72.20; H, 9.92; N, 3.85. Found: C, 72.20; H, 10.23; N, 4.09.

(b) N-(3-phenyl-3-cyclohexyl-2-ethy1propyl) piperidine:

A mixture of 65.8 g. of l-phenyl-l-cyclohexyl- 2-(N-piperidyl1nethyl)-l-butanol, 10 g. of red phosphorus, 70 cc. of 47% hydriodic acid and 200 cc. of glacial acetic acid was caused to react in the manner described in Example 1, part (b). The crude basic product was converted directly to its hydrochloride and crystallized from an alcohol-ether mixture. The first crop, about 12 g., had the M. P. 198-202 C. which, when recrystallized from sec.butyl alcohol using ether as a precipitant, gave a sample of one of the racemates of the hydrochloride of N-(3-pheny1-3- cyclohexyl 2 ethylpropyl) piperidine, M. P. 211.5-213 C.

Anal. Calcd. for C22H3sNC1: Cl, 10.13; N, 4.00. Found: Cl, 10.00; N, 4.04.

The other racernate was obtained in the following manner: the mother liquors from the original first crop of hydrochloride were evaporated, and the residue was recrystallized from sec.-butyl alcohol using ether as a precipitant. A first crop of 7 g., M. P. -180 C. was obtained, and, upon concentration, a second crop of 31 g., M. P. 138-145 C. When this second crop was recrystallized from ethyl acetate, 22.5 g., M. P. l45-l51 C., was obtained. Careful fractional crystallization of this product from toluene using ether as a precipitant gave 8 g. of the other racemate of the hydrochloride of N -(3- phenyl-3-cyclohexyl-Z-ethylpropyl) piperidine,

which contained the free base was separated, the 75 M. P. 148.5- C.

" (dec .aaceassc 9 Anal. .Calcd.. fonCzHseNCl: .C1, 10.1 3 N, .400.

..Eound :-.C1 10.16 N, 3.85.

"cExamplez a a). "'Phenylisobutylacetonitrile :TiBenzyl cyanide (293 g'.) was addedgradually tea stirred suspen- .sion f.115 g. of sodium amidelin 250;cc. of dry I..benzene .at 40-'-50 C. "The mixturewasstirred at mm.) n- =1.497-8:85, was collected.

(1)) Phenylisobutyl (N piperidylethyll-acetonitrile:

"CH3%CIH-":'CH3

H2 .o.H.-lo cH.cHlNc.Hm

A stirred suspension of 18 g; of sodium amide in a solution of 26' g. of phenylisobutylacetonitrile in 200 cc. of dry benzene was heated to 65 C. for

a few minutes. Themixture-was then cooled to about 30 C.,-and?!.G g.*of'N-piperidylethyl chloride hydrochloride was added. After refluxing for two hours, themixture was cooled and the excess sodium amidewas hydrolyzed by addition of alcohol and water. "The'organic "layer was separated and washed with water and dried over anhydrous sodium sulfate. .The product was distilled at reduced pressure giving 34 g. (80%) of phenylisobutyl-(N-piperidylethyl) acetonitrile, B. P. 136-142 (0.04 mm.), n =1.5140.

Its hydrochloride had the M. P. 193-195 0.

Anal. Calcd; for C19Hz9N'2Cl:-' C; 71.11; H, 9.11;

Found: C, 71.1 6111,-9;00;*N,-'8.65. Its methiodi'de'prepared by heating a sample of' the free base with an excess of methyl iodide in benzene solution and "recrystallization from ethyl acetate, had the MI P. 17 1-1'73" 0.

Anal. Calcd. forC2oH31N2I:-'C, 56;33; H, 7.33;

A stirred suspension of 25 g. of sodium amide in 100 cc. of dry xylene was heated to reflux, and 26 g. of phenylis-obutyle(N piperidylethyl)-ace-tonitrile was slowly added over a period of one hour. The mixture was refluxed andastirred 'fcr '-ten hours; then cooled and 100 cc. ofwater was added to hydrolyze excess sodium amide. organic layer wasseparated and -the aqueous layer extracted withe'ther which was-then*com-' bined with the original organic layer. =-The 'corn- The binedextracts were washed twice w'ith water (which was discarded) and then *witha solution of L 100, cc. of concentrated hydrochloric" acid in I "100 cc..of watenand "finally" twice with water. The. combinedacid solutions, which contained the hydrochloride of the'desired product, were shaken twi e with .ethersa-ndzthen made :alkaline with sodium hydroxide. The. liberated freebase.

precipitating with anhydrous ether. tained in about yield and had the M. R1203- ..205 C. .A purer product was obtained by re- .wasextractedwithether, dried over sodium hydroxide pellets anddistilled giving 21.3 g. (90%) .of N-(S-methyL-B-phenylhexyl)-piperidine, B. P. 103-10'7 C. (0.25 mm.), n =1.5035.

The hydrochloride was prepared by dissolving the. free base in alcoholic hydrogen chloride and It was obcrystallization from isopropyl alcohol giving a sample with the M. P. 206-207 C.

Anal. .Calcd. fOlCmI-IsbNCl: C, 73.06;.H, 10.22;

-N, 4.73. Found: (2,7332; H, 9.97; N, 4.60.

N. (5-methyle3-phenylhexyl) -piperidine was converted to its. methiodide in the following man- ..ner: a s-olutionof 15.6 g. of the free hasean'd' 12.6 ,g. of.-methy1f iodide in drybenzene was-warmed until an oil separated. This -.was.induced to crystallizeby diluting with an equal volume of ethyl acetate,-filtered, washed with ethylacetate -anddrled, giving22g. (92%), M. P. 102103 .C.

Recrystallization from an ethyl acetate-methanol mixture gave a puresampleofthe methiodide;'M. P. 103-104.5 C.

Anal. -Calcd. for C19H32NI: .C, 56.85; 8.04; I, 31.62. .Found: (1.57.08; H, 7.91; I, 31.60.

Example 4 (a) Phenylcyclohexyl (N piperidylethyl)- acetonitrile CuHu CaH-G-rQHzCHzNCsHm A stirred suspension of 50 g. of sodium.-amide in a solution of 216.2 g. of phenylcyclohexylacetonitrile (Organic. Syntheses .25,. 25) in 200 cc. of

dry benzene, was heated to 65 C. fora few minutes. The mixture was then cooled to about 30 C; and 16225 g.*of N piperi-dylethylchloride was added. After refluxing for two hours, the-mixture was cooled and the excess sodium amide-was hydrolyzed by addition of alcohol and water. The organic layer was separated and washed with water and dried over anhydrous sodium'sulfate. The product was distilled at reduced pressure 'giving'246 g.--of phenylcyclohexyl-(N-piperidylethyl) -acetonitrile, nb =1.5345.

.Its. hydrochloride, prepared from the free base "and'alcoholic hydrogen chloride, had the r/I. P. -230-232 C. (dec.).

Anal. "Calcd."forCziHznNzClr' N,8.08; 01.10.22. Found; N, 8.12; Cl, 9.96.

(b) N (3-phenyl-3-cyclohexy1propyl)-piperidine:

\ GaHu "was: prepared by a method analogous to thatde :scribdfzin 'Example 3, part (c). 60'

anda suspension of 80 g. ofsodium amidein'500 -Phenylcyclohexy1-(N=piperidylethyl)-acetonitrile (155.3 'g.)

cczof'xy-lenegave a'pro'duct,'B,'P. 132'l37 C. (0.05'mm.),"n,; =1;5274. When converted to its hydrochlorideby the alcoholic hydrogen'chloride- 65 ether'metho'd, 145g. of product, M. P.225-226FC.

was obtained. Recrystallization of this from an .rtalcohol ethyr-acetate' mixture gave gnof the hydrochloride of N (3 phenyl-S cycl'ohexylpropyl) -piperidine, 227-228C.

Anal. Calcd. for'GrloHi'zNCl: N, 4.35; 01, 11.01. 'Found:-"N,.-4-.31; Cl; 10.97.

Example 5 (a) N (3,3 -rdiphenylprcpyl) piperidine (see Bockmuhl et al., U. S. Pat.i2,446,522) A mixture of 336 g. of diphenylmethane and 235 g. of chlorobenz-ene was introduced drop by drop, while stirring, into 106 cc. of benzene containing 101 g. of finely cut sodium wire. The temperature kept at about 35 C. by occasional cooling. After about seven to eight hours the reaction was fin ished. Thereupon, 240 g. of N-piperidylethyl chloride was added dropwise, the whole was stirred for one hour at room temperature and finally heated for one hour under reflux. The mixture was then cooled, water added, the benzene layer separated and extracted with dilute hydrochloric acid. The acid solutions were made alkaline with sodium hydroxide solution, and the free case which separated was extracted with ether and distilled at reduced pressure, giving an oil boiling at 210220 C. (8 mm.). Its hydrochloride had the M. P. 214-215 C.

(b) N (3-phenyl-3-cyclohexylpropyl) piperi dine: A solution of 19.5 g. of N-(3,3-diphenylpropyl) -piperidine in 150 cc. of glacial acetic acid was shaken with 0.5 g. of Adams platinum oxide catalyst at room temperature in an atmosphere of hydrogen. at 6? lbs. pressure. After about a day no additional uptake of hydrogen was observed. Distillation of the product gave 18.9 g. of N-(3phenyl--3-cyclchexylpropyl) -piperidine, B. P. 160-167 C. (0.75 mm). The hydrochloride had the same melting point as the product of Example 4, part (b) and a mixed melting point showed no depression.

Example 6 (a) Phenylcyclohexyldimethylaminoethylacetonitrile,

C tHn C H5 +C H2CH2N( CH3):

was prepared by a method similar to that described in Example 3, part (c) The reaction of 40.5 g. of phenylcyclohexyldimethylaminoethylacetonitrile and g. of sodium amide gave 31.2 g. (85%) of 3-phenyl-3-cyclohexylpropyldimethylamine, B. P. 105-124 C. (0.25 mm.), 12 215150.

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 31.2 g. of free base gave 28.3 g. of the hydrochloride, M. P. 151-154 C. Recrystallization from alcohol, using ether as a precipitant, gave a pure sample of the hydrochloride, M. P. 154.5-156" C.

Anal. Calcd. for C17H28NC12 N, 4.97; Cl, 12.58. Found: 'N, 4.91; Cl, 12.44.

Example 7 (a) Phenylcyclohexyl (N pyrrolidylethyl) acetonitrile,

12 was prepared by a method similar to that described in Example 4, part (a). The reaction or 139.5 g. of phenylcyclohexylacetonitrile, 83.5 g. of N-pyrrolidylethyl chloride and 40 g. of sodium amide gave 193 g. of crude basic product which was used directly in the next reaction.

The hydrochloride of phenylcyclohexyl-(N- pyrrolidylethyl) -acetonitrile has the M. P. 194.5- 196 C.

Anal. Calcd. for CzoHzeNzCl! Cl, 10.65; N, 8.42. Found: C1, 10.61; N, 8.31.

(b) N-(3-phenyl-3-cyclohexy1propyl) -pyrrolidine,

was prepared by a method similar to that described in Example 3, part (c). The reaction of 59.4 g. of phenylcyclohexyl-(N-pyrrolidylethyl) acetonitrile and 40 g. of sodium amide gave 41 g. of N- (3-phenyl-3-cyclohexylpropyl) -pyrrolidine, B. P. 126-130 C. (0.1 mm), n :1.5278.

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 26.8 g. of the free base gave 22.2 g. of hydrochloride, M. P. 181-182.5 C. Recrystallization from acetone, using ether as a precipitant, gave a pure sample of the hydrochloride, M. P. 181.5- 183 C.

Anal. Calcd. for C19H30NC12 C, 74.11; H, 9.82; CI, 11.51. Found: C, 74.33; H, 9.66; Cl, 11.38.

Example 8 (a) Phenylcyclohexyldiethylaminoethylacetonitrile,

CeHu

C tHs-U CH2C H2N( 02115):

was prepared by a method similar to that described in Example 4, part (a). The reaction of 207.3 g. of phenylcyclohexylacetonitrile, 144.4 g. of diethylaminoethyl chloride and 48.4 g. of sodium amide gave 256 g. (82%) of phenylcyclohexyldiethylaminoethylacetonitrile, B. P. 174- 182 C. (2 mm.), n ::1.5187.

Its hydrochloride had the M. P. 157-158 C.

Anal. Calcd. for C20H31N2C1: N, 8.37; Cl, 10.59. Found: N, 8.36; Cl, 10.60.

Its methiodide had the M. P. 169-170 0.

Anal. Calcd. for C21H33N2I; C, 57.26; H, 7.55; N, 6.36; I, 28.82. Found: C, 57.09; H, 7.34; N, 6.22; I, 28.35.

(b) 3-phenyl-3-cyclohexylpropyldiethylamine,

CoUu

CeHs-C H-CH2C HEN C2315)? was prepared by a method similar to that described in Example 3, part (c). The reaction of 59.7 g. of phenylcyclohexyldiethylaminoethylacetonitrile and 31.2 g. of sodium amide gave 45.2 g. (82%) of 3-phenyl-3-cyclohexylpropyldiethylamine, B. P. -163 C. (1.5 mm.), n :1.5120.

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure. The crude product when crystallized twice from anhydrous alcohol using anhydrous ether as a precipitant, gave a pure sample of the hydrochloride, M. P. 125.5-127 C.

Anal. Calcd. for C19H32NC1: C1, 11.45; N, 4.52. Found: C1, 11.32; N, 4.45.

.butyldithylaminoethylacetonitlile, YI'B. I P. 114- I 118"C. (0.05.111111.) ni :1.4960.

was collected by filtration, and the -resulting 'benzochloride .of phenylisobutyldiethylaminoethylacetonitrile was recrystallized froma methtrile,

' 113 Examplef-t (a) Phenylisobutyldiethylaminoethylacetonitrile,

C H5. H- 0 Ha H2 CnH5-( J-CI '::CH2N(C2H5)2 was prepared by a method similar to that described in Example 4, part (a). The reaction of 86.7. g.. of phenylisobutylacetonitrile; (Example 3,

part (a) ,65 g. of. diethylaminoethyl chlorideand 50 g. of. sodium .amide gave 110 g. of .phenyliso- Its hydrochloridehadjthei. MJP; 133i-L1343TC.

Anal. Calcd. for CmHzs'NzClz' N; 9.07;"Cl, 11.48. Found: N, 9.09; Cl, 11.42.

Its methiodidehad1the M. P. 155.5-157" 0.

Anal. Calcd. for .C19HsiN2I:.--N,. 6.'76;..I, 30.63.

llound:.N,. 6.72; I,.30.60.

, Its. benzochloride :Was prepared, as. follows A mixture of 19.1 g. of phenylisobutyldiethylamino- -ethylacetonitrile, 9.9 g. or" benzyl chloride and.75

ml. of ethyl acetate was heated on asteam bath for three hours. Then part of theethylacetate was evaporated and etheradded whereupon a crystalline solid precipitated. This suspension anol-ether mixture giving 6.7-g., M.P. 162-164 C. (uncorrected) Its ethobromide was preparedasfollows: -A mixture of 19.1 g. of the nitrile and 33 g. of ethyl bromide was heatedat about C. for ten days.

. The excess of cethyl 'bromide was .-..evaporated and the residue was :recrystallized from an cetonea-ether mixture giving .the ethobromide 10f 1phenylisobutyldiethylaminoethylacetonitrile,

Mr-P. 135-.5e13'7 C. (uncorri).

. .(b) N,N -.diethyl--.5 methyl-.Bzphenylhexylamine,

vons-ca-ona "CH2 cseb-cn-cmonmwaem was prepared by a method similar'to'thatf'described in Example 3, part (c). The reaction of Anal. Calc'd. forCrvI-IaoNCl: C, 71.93 ;;-H;. 10.65; X

"C1. 12.49. "Found; 0,172.12; :H, 10.58;..C1,;'12.30.

N,N diethyl-5.-.methy1 413 aphenylhexylamine was converted to its'methiojdidaby'.thezmethod described in Example 58, part i .(c) 14.5 gsnof. the free base and 126g.- of:.methyl.:iodide gave. 21.3 g. of methiodide, M. 'P.;111'-1l3'C. Recrystallization from'a; methanol-ethyl acetate mixture gave a pure sample of the .methicdide,. M.?P. 11425-11? C.

Anal. Calcd. for CisHszNI: 55.52; H, 8.28; I, 32.60. Found: C, 55.57; H, 8.23; I, 32.56.

Example 10 1 (a) Phenylisobutyldimethylaminoethylacetcninwascprepard byua methodz similar" to thatsde- .escribedtinlijExample4, part a .(a) rot 86.7.1: grof phenylisobutylacetonitrile; 54 g. z of 'idiznethylaminoethyl; chloride and 30 .g. of. sodi- The reaction um amidegave 71.6 .g; of phenylis'obutyldimethylaminoethylacetonitrile, B. P. 112-120 C. (0.4 mm.); n =1.5020.

"Its-hydrochloride had the M. 1 3242-243 C. -Anal. i calcd. for "CiHaN'Cl :"C; 68.43;" H,f8'.97;

(b) N,N,5-trimethy1-3 -phenylhexylamine,

.. CJHaTCH- OHa G'Hz imm-H-G'Hiommdm)z 'wasprepared' bya method similar to thatde- "scribed in Exam'ple 8, part (c).

of 48.9 g. of phenylisobutyldimethylaminoethylacetohitrileand-AOg. of sodium amide ga /e395 g. (90%) of N,-N-dimethyl 5-methyl-3-phenyl- The reaction hexylamine, B. P. 71-75 C. (0.8mm);

The hydrochloride-was. prepared by the usual alcoholic hydrogen chloride-ether procedure;

2119.95; of the free basegave2lg. of hydrochloride,

ML P. "134-139 0 Recrystallizationi'from' ethyl acetate'gave at pure sample of the hydrochloride, M: P. 186-137 C.

Anal. calm-forcaramel t 70.42 i H, 1024;

-01; 13 .86. *Foundro, vomy-nyioee; 01, 13.57.

"verted to'itsmethiodide by the method described N,Ni-5-trimethy1 3=phenylhexylamine was coninExamblBypart (c) 13.1 g of the free base and iodide. Recrystallization from benzene "gave a pure sample of the methiodide, M. P. 109-111 C.

Anal. Ca1Cd..fOr.C16H28NII.C,' 53.18; H, 7.31; I, 35.13. Found: C, 53.30; H, 7.69; I, 34.86.

. Example .11

1((1)1Phenylcyclopentylacetonitrile was prepared firombenzylcyanide and cyclcpentyl bromide by eprocedure analogous tojthat described inOr- ,ganiciSyntheses, vol. 25,, p. 25 for phenylcy'clohexylacetonitrile. if It was obtained in about',-5'7% ...yield, B- P. 101-107 0. (0.05-05 mm.);

(b) Phenylcy'clopentyldimethylaminoethylacetonitrile,

.101110 czcxm- (Home HiN(GBs)z was zpreparedibyzz a method A similar to that 1. de- -;scribe.d..=Example ';.4, :.part (a) The reaction of 64.8 g. of .phenylcyclopentylacetonitrile,87.7

: ,g; :of..dimethylaminoethyl .chloride' anol 20 g. of .sodiumaamidecgarref 66' 1g: of;.phenylcyclopentyldimethylaminoethylacetonitrile, P. 134-141 C. x 11.0mm.) ami -1.5210.

1 c) N,N-dimethyl-3-phenyl-3-cyclopentylpropylamine,

C6H5CH CH2CH2N(OH3)2 was prepared by a method similar to that described in Example 3, part (c). The reaction of 50.4 g. of phenylcyclopentyldimethylaminoethylacetonitrile and 40 g. of sodium amide gave 37 g. of N,N-dirnethy1-3-pheny1-3-cyclopentylpropylamine, B. P. 103-103 C. (0.25 mm);

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 18.7 g. of free base gave 20.4 g. of hydrochloride, M. P. 134-136 C. Recrystallization from anhydrous alcohol using ether as a precipitant gave a pure sample of the hydrochloride, M. P. 137-139 C.

Anal. Calcd. for CmHzcIIClI C, 71.75; H, 9.79; C], 13.24. Found: C, 71.46; H, 0.82; Cl, 13.33.

N,N-dimethyl-B-phenyl 3 cyclopentylpropyh amine was converted to its methiodide by the method described in Example 3, part (c) 10.5 g. of the free base and 14 g. of methyl iodide gave 16.8 g. of the .1 ethiodide, IVE. P. 129-132 C. Recrystallization from ethyl acetate con ing a trace of ethanol gave apure sample of the methiodide, M. P. 1345-1365 C.

Anal. Calcd. for Chi-12311;: C, 54.60; H, 7.56; I, 34.00. Found: C, 54.60; PI, 7.46; I, 33.80.

Example 12 (a) Alpha-phenylcaprylonitrile was prepared by a method similar to that used for the preparation of phenylisobutylacctonitrile, described in Example 3, part (a). The reaction of 292.5 g. of benzylcyanide, 406 g. or" n-hexyl bromide and 115 g. of sodium amide gave a crude product which, r. .en fractionally distilled at reduced pressure, gave 310 g. (60%) of alpha-phenylcaprylonitrile, B. P. 95-107" C. (0.1-0.2 mm), n =1.4955.

(b) Phenyl- (n-hexyl) -diethylaminoethylacetonitrile,

was prepared by a method similar to that described in Example 4, part (a) The reaction of 201.2 g. of alpha-phenylcaprylonitrile, 135.6 g. of diethylaminoethyl chloride and 48.4 g. of sodiurn amide gave 210 g. (70%) of phenyl-(nhexyl)-di thylamincethylacetonitrile, B. P. 138- 142" C. (0.15 rum); n :l.4936.

Its hydrochloride had the M. P. 103-105 C.

Anal. Calcd. for CaiiiaNzClzN, 8.31; CI, 10.52. Found: N, 8.30; Cl, 10.70.

(c) N,N-diethyl-3-phenylnonylamine,

was prepared by a method similar to that described in Example 3, part (c). The reaction of 60 g. of phenyl-(n-hexyl)-diethylaminoethylacetonitrile and 31.2 g. of sodium amide gave 39.4 g. of N,i -diethyl-3-phenylnonylamine, B. P. 126-130" (1.0 mm); n =1.4860.

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 33.6 g. of free base gave 24.5 g. of hydrochloride, M. P. 875-89 C. It was recrystallized by dissolving in cc of anhydrous ethanol and adding 100 cc. of anhydrous ether to give a pure sample of the hydrochloride, P. 89-895 C.

16 Anal. Calcd. for C1QH34NCI: N, 4.49; Cl, 11.33. Found: N, 4.56; C1, 11.17.

Emample Z 3 (a) Phenyl n hexyl (N piperidylethyl) acetonitrile,

CsHu

CuHs-(|3-CH2CHzNC5Hm was prepared by a method similar to that described in Example 4, part (a). The reaction of 149.2 g. of alpha-phenylcapry1onitrile, 118.2 g. of piperidylethyl chloride and 45.0 of sodium amide gave 113 g. of phenyl-n-hexyl-(N-piperidylethyl)-acetonitrile, B. P. 165-170 C. (1 mm).

(b) N- (3-phenylnonyl) -piperidine,

CfiHlS CeH5CHCHzCHzNC5Hm was prepared by a method similar to that described in Example 3, part (c). The reaction of 87.6 g. of phenyl-n-hexyl-(N-piperidylethyl) acetonitrile and 43 g. of sodium amide gave 62.8 g. (7 8%) of N-(3-phenylnonyl)-piperidine, B. P. 124-132 C. (1 mm.); n :l.5010.

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 21.5 g. of the free base gave 21.1 g. of hydrochloride, M. P. 179-180 C. Recrystallization from isopropyl alcohol, using ether as a precipitant gave a pure sample of the hydrochloride, M. P. 180-180.5 C.

Anal. Calcd. for C21H33N2C1Z C, 74.15; H, 10.58; N, 4.32. Found: C, 73.90; H, 10.50; N, Example 14 (a) Phenyl-(Z-methylallyl)-acetonitrile was prepared by a method similar to that used for the preparation of phenylisobutylacetcnitrile, dcscribed in Example 3, part (a). The reaction of 292.5 g. of benzyl cyanide, 226.5 g. of 2-methy1allyl chloride and g. of sodium amide gave a mi ture of monoand disubstituted products which were separated by repeated fractionation through an eiiicient packed and heated Vigreux column until a fraction boiling at l23-131 C. (5 mm); n :l.5185, was obtained; total yield about g.

(b) Phenyl (2 methylallyl) (N piperidylethyl) -acetonitrile,

was prepared by a method similar to that described in Example 4, part (a). The reaction oi 146.2 g. of phenyl-(2-methylallyl)-aoctonitrile, 144.8 g. of piperidylethyl chloride and 60 g. of sodium amide gave 174 g. of phenyl-(Z-methylallyl)-(N-piperidylethyl)-acetonitrile, B. P. 141- C; (1 mm.) n :1.5258.

The hydrochloride had the M. P. 2l3-214 C.

Anal. Calcd. for C19H27N2C12 C, 71.56; H, 3.54; N, 3.79. Found: C, 71.65; H, 8.51; N, 8.54.

(c) N (5 methyl 3 phenyl 5 hexenyl) -piperidine,

was prepared by a method similar to that described in Example 3, part (c). The reaction of 65.8 g. of phenyl-(2-methylallyl)-(l-l-piperidyl- I?" ethyl) trile and 36-3, e. of amide gave 29 g. of N-.(-methyl-3-phenyl-5-hexenyl)- piperidine, B. P. 102-114" C. (1.0 mm.);

The. ydr chloride was, smeared by he usua alcoholic hydrogen chloride-ether procedure; w en e rysta z d, i em opre yl. bo the hydrochloride melted at 199-200 C.

Anal. Calcd. for C1sH2sNCl1C, 73.56; H, 9.60; N, 4.76. Found: C, 72.77; H, 9.26; N, 4.59.

Example 15 (a) Phenyl (2 methyl 1 propenyl) (N- piperidylethyl) -acetonitrile,

was prepared by a method similar to that described n E mp e ar T e ea on f 85.6 g. of isobutylidene-phenylacetonitrile [Murray and Cloke, J. Am. Chem. Soc. 58 2016 (1936) 92 g. of piperidylethyl chloride hydrochloride and 50 g. of sodium amide gave 106 g. (75%) of p yl (2 th l. 1 p per yh (N piperldylethyD-acetonitrile, B. P. 136-139" C (0.05 mm.); n :1.5260.

Its hydrochloride had the M. P. 203-2045 C.

Anal. Calcd. for C19H27N2C1: Cl, 11.12; N, 8.79. Found: Cl, 11.12; N, 8.60.

Its methiodide had the M. P. 199.5-201 C.

Anal. Calcd. reroute-281x21: N, 6.60; I, 29.91. Found: N, 6.48; I, 29.85.

(b) N (5 methyl 3 phenyl 4 hexenyl) piperidine,

CH: -CH,: mm-dn-ornonmmm was prepared by a; method similar to that described in Example 3, part (c). The reaction of 70.8 g. of phenyl-(Z-methyl-l-propenyl) -(N- piperidylethyl)-acetonitrile and 45 g. of sodium amide gave 33 g. of N..-(5-methyl-3-pheny1-- hexenyl) -piperidine, 13. P. 114-116 C. (0.05 mm.) n 1.5'195. 7 V

The hydrochloride was prepared by the usual alcoholic hydrogen chloride-ether procedure; 33 g. of the free base gave 30 g. of hydrochloride, M. P. 195.5.-.l97 C. Recrystallization from anhydrous alcohol using anhydrous ether as a precipitant gave a pure sample of the hydrochloride, M. P. 198-200 C. Absorption spectra. data indicated no conjugation of the double bond with the phenyl ring.

Anal. Calcd. for CisHzaNClz C, 73.56; H, 9.60; C1, 12.07. Found: C, 73.41; H, 9.60; Cl, 11.90.

N (5 methyl 3 phenyl 4 heXenyD- piperidine was converted to its methiodide by a m t d im to that d s ribed in xample 3. Pa (C) a of e ree ase and 9 of me yl iodide gave 14.6 g. of the methioolide, M. P. 1235-- 125 C. Recrystallization from an ethyl acetatemethanol mixture gave a pure sample of the methiodide, M. P. 127.5-129.5 C.

Anal. Calcd. for C19Ha0NI: C, 57.14; H, 7.57; I, 31.78. Found: C, 57.43; H, 7.59; I, 31.60.

We claim:

1. A member of the group consisting of a compound of the formula 18 wherein Risa member of the. group consisting of alkyl and alkenyl radicals .of 4.16. carbon. atoms and 5-6-membered cycloalkyl radicals, Y- is a lower alpha,beta-allgylene radical, and N=EB is a member or: the group consisting of di-loweralkylamino, piperidino, morpholino and pyrrolidino groups; and water-soluble, non-toxic salts thereef- 2-. A. temp e- 1nd o th tem e.

CuHj; .R

wherein R is cyclohexyl, Y is a lower alpha,betalky ene r i nd R. n B" a e lower a k rad qe 3. A compound of the formula 0.13. CHY.N

R RI! wh re R is n e ir radiee 9 :6 carbon $91 Y is a lower alpha,beta-alkylene radical, and R n R" are lower a l r ps 4. N-(5-methyl 3 phenylhexyl) piperidine having the formula CuHs CH2CH2 CH3 CH-OHgOHz-N CH CHTGHQ se se; C35

5. The process for preparing a compound of the formula CaH5 "oH-Y-N=B h m n oH-oN wi h an. em nqe ky halid 9? t e o mu a X -Y .N= w erein X1 halo en. in t e res ence of sodium amide, and subsequently replacmg h W ou w hydr e b atin w t di m a 6. A compound of the formula aHs R OH-CHaCHzN wh rei i n alkyl rad ca o 4-6 c bo atoms, and R and R" are lower alkyl groups 7. The method of preparing l-phenyl-l-cyclohexyl-3-piperidinopropane which comprises the steps of alkylating pentylcyclohexylacetonitrile w th a p peridinoethyl halide in the presence of sodamide and subsequently replacing the cyano group with hydrogen by heating the resulting phenylcyclohexylpiperidinoethylacetronitrile with sodamide.

8. A compound of the formula 19 wherein R is cyclohexyl and Y is a lower alpha,- beta-alkylene radical.

9. A compound of the formula wherein R is an alkyl radical of 4-6 carbon atoms and Y is a lower alpha,beta-alkylene radical.

10. A compound of the formula Ca s CHzCH:

CHCH:CH2N /CH1 R CHzCH:

wherein R is an alkyl radical of 4-6 carbon atoms. 11. The process of preparing a compound of the formula wherein R is an alkyl radical of 4-6 carbon atoms and Y is a lower alpha,beta-alkylene radical, which comprises alkylating a compound of the formula CH-CN with a piperidinoalkyl halide of the formula X-YNC5H10, wherein X is halogen, in the presence of sodium amide, and subsequently replacing the cyano group with hydrogen by heating with sodium amide.

12. The process for preparing a compound of the formula R RI! wherein R is cyclohexyl, Y is a lower alpha,betaalkylene radical, and R and R are lower-alkyl radicals, which comprises alkylating phenylcyclohexylacetonitrile with an aminoalkyl hal.de of the formula X-YNRR", wherein X is halogen, in the presence of sodium amide, and subsequently replacing the cyano group with hydrogen by heating with sodium amide.

13. The process for preparing l-phenyl-l-isobutyl-3-piperidinopropane, which comprises alkylating phenylisobutylacetonitrile with a piperidinoethyl halide in the presence of sodamide and subsequently replacing the cyano group with hydrogen by heating the resulting phenylisobutylpiperidinoethylacetonitrile with sodamide.

14. l-phenyl 1 cyclohexyl-3-(l-piperidino) propane.

15. l-phenyl 1 cyclohexyl-3-(l-piperidino) propane hydrochloride.

16. 3-phenyl-3-cyclohexylpropyldimethylamine having the formula CIZoHu 20 18. A compound of the formula 00H: /R' CHCH2CH:N

wherein R is cyclohexyl and R and R" are lower alkyl radicals.

19. The process of preparing a compound of the formula RuHs R wherein R is an alkyl radical of 4-6 carbon atoms, Y is a lower alpha,beta-alkylene radical, and R and R are lower-alkyl groups, which comprises alkylating a compound of the formula CaHl CH-CN with a dialkylaminoalkyl halide of the formula XYNR'R", wherein X is halogen, in the presence of sodium amide, and subsequently replacing the cyano group with hydrogen by heating with sodium amide.

20. The process of preparing a compound of the formula CoHs CHiCH:

CH-YN\ /CH1 R CHzCH:

wherein R is cyclohexyl and Y is a lower alpha,- beta-alkylene radical, which comprises alkylating a compound of the formula CsHS CHCN

with a piperidinoalkyl halide of the formula XYNC5H10, wherein X is halogen, in the presence of sodium amide, and subsequently replacing the cyano group with hydrogen by heating with sodium amide.

ARLO WAYNE RUDDY. MAURICE L. TAINTER,

Administrator of the estate of Theodore J.

Becker, deceased.

Suter et al.: Jour. Amer. Chem. Soc., vol. 64 (1942), pp. 533-6.

Cohen et al.: Jour. Chem. Soc. (London), vol. 107 (1915), pp. 901 and 902.

Mannich: Ber. der Deu. Chem, vol. 69 (1936), p. 2113. 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 